In glaucoma, there is no science to predict what level of intraocular pressure (IOP) will be safe for a given optic nerve head (ONH). The goal of this project is to identify the clinically important components of optic nerve head (ONH) susceptibility to glaucomatous damage using basic engineering principles. The proposed biomechanical studies test the following hypotheses within high-resolution, digital, three dimensional (3D) reconstructions (1.5 x 1.5 x 1.5 urn voxel) and finite element models (FE Models) of the normal and glaucomatous ONH: 1) The distribution of stress (force/cross-sectional area) and strain (local deformation) within the lamina cribrosa and peripapillary scleral of the Normal ONH predicts the sites of connective tissue damage in Early Experimental Glaucoma; 2) At all levels of IOP, strains within the remaining connective tissues of Early and Moderate but not Severe Glaucoma eyes are higher than in Normal eyes; 3) A predictable pattern of fixed (permanent) deformation of the ONH connective tissues underlies the onset and progression of glaucomatous cupping in Early, Moderate and Severe Glaucoma but is not present in the optic neuropathies of Early and Late ONH Ischemia and Optic Nerve Transection; 4) the ONH connective tissues of Old eyes are hardened compared to those of Young eyes and this difference in ONH connective tissue stiffness affects the clinical behavior of the Aged, Glaucomatous ONH. The Specific Aims and Objectives are: 1) To expand our continuum and micro FE Modeling of the ONH tissues to Severe Glaucoma and to the Young and Very Old Normal ONH; 2) To perform 3D histomorphometry within the digital 3D geometries of Normal Young and Very Old, Early, Moderate and Severe Glaucomatous, Early and Late Ischemic and Optic Nerve Transection ONH so as to characterize and compare the 3D patterns of connective tissue architecture and damage; 4) To test the hypothesis that the ONH connective tissues of the Aged ONH are less susceptible to deformation than those of the Young ONH and that this difference in susceptibility affects the clinical appearance and behavior of the Aged ONH at the onset of glaucomatous damage as seperately defined by structural and functional criteria. The methodology includes longitudinal ONH surface change detection using Heidelburg Retinal Tomographic Change Analysis; multifocal Electroretinogram (mfERG) testing; high-resolution, 3D reconstruction and 3D histomorphetry of the ONH neural and connective tissues; automated optic nerve axon counting; 3D material properties testing of intact posterior scleral shells; and continuum and micro FE modeling of the ONH neural and connective tissues. [unreadable] [unreadable] [unreadable]